Mononuclear phagocytes MPs play crucial roles in the initiation of innate and adaptive immune responses and in the maintenance of tissue homeostasis. Although MPs share several phenotypic and functional characteristics, it has recently become clear that dendritic cells (DC), macrophages (Mac) and monocytes (Mo) are not homogeneous populations and instead they represent developmentally and functionally distinct populations that differentially regulate T cell function. MPs are major components of the tumor microenvironment where they play a dual role inducing adaptive anti-tumor responses but also sustaining immune evasion, tumor progression, and metastasis formation. Despite major advances in the identification of the MPs developmental pathways and their transcriptional regulation, the individual contribution of these distinct cell subsets to the induction and resolution of immunity against invading pathogens, or to anti-tumor responses or immune evasion, as well as the environmental signals involved in their regulation remain unclear. In this project we will use murine experimental tumor models to investigate the mechanisms regulating MP differentiation and function, with particular emphasis on the role of the commensal microbiota. Local and systemic inflammation modulates cancer susceptibility (e.g. in obesity), cancer progression, response to therapy, and co-morbidity (e.g. cancer cachexia/anorexia). The microbiota influences both immune and metabolic function beyond the gut, including peripheral innate cell responses, autoimmunity and response to viral infections. In recent studies we have shown that gut commensals control the response of subcutaneous tumors to immunotherapy and chemotherapy by modulating tumor infiltrating MP function (Science 2013, 342:967-970). This study demonstrates the novel finding that and intact gut microbiota is needed for optimal response to cancer therapy and underscores the potential to improve cancer treatment by manipulating the gut microbiota. However, the exact molecular mechanisms by which commensal bacteria modulate systemic inflammation are still unknown. We will use several approaches to address this question performing parallel studies in cancer and infection models. We will utilize the germ-free (GF) facility at NCI-Frederick to compare conventionally reared and GF animals under steady state or different inflammatory settings. The laboratory was established in April 2015, and in the past four months we have made significant progress towards hiring personnel, acquiring equipment and developing techniques that will allow us to achieve these goals